JP2014129358A5 - - Google Patents

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JP2014129358A5
JP2014129358A5 JP2014016227A JP2014016227A JP2014129358A5 JP 2014129358 A5 JP2014129358 A5 JP 2014129358A5 JP 2014016227 A JP2014016227 A JP 2014016227A JP 2014016227 A JP2014016227 A JP 2014016227A JP 2014129358 A5 JP2014129358 A5 JP 2014129358A5
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細胞溶解は、典型的にはホモジナイゼーション又はヘッドミル等の機械的破壊技術を用いて達成される。対象のタンパク質は一般に効率的に遊離されるが、そのような技術には幾つかの欠点がある（Engler, Protein Purification Process Engineering, Harrison編, 37-55 (1994)）。処理の間にしばしば温度が上昇し、タンパク質の不活性化が起こる場合がある。更に、得られた懸濁液が幅広いスペクトルの汚染タンパク質、核酸及び多糖類を含む。核酸及び多糖類により溶液の粘度が増大し、引き続いて行われる遠心分離、クロスフロー濾過、又はクロマトグラフィーによる処理が困難となる可能性がある。これら汚染物質が対象のタンパク質と複雑に関連することにより、精製プロセスが複雑化し、その結果十分な産生量が得られない場合がある。微生物発酵ブロス又はホモジネートからの異種性ポリペプチドの改良された精製法は、例えば、その全開示が出典明示によりここに明示的に援用される米国特許第７１６９９０８号に記載されている。
Cell lysis is typically achieved using mechanical disruption techniques such as homogenization or head mill. Although the proteins of interest are generally released efficiently, such techniques have several drawbacks (Engler, Protein Purification Process Engineering, edited by Harrison, 37-55 (1994)). Often the temperature rises during processing and protein inactivation may occur. Furthermore, the resulting suspension contains a broad spectrum of contaminating proteins, nucleic acids and polysaccharides. Nucleic acids and polysaccharides increase the viscosity of the solution, which can make subsequent processing by centrifugation, crossflow filtration, or chromatography difficult. These contaminants are complexly associated with the protein of interest, which complicates the purification process and may not result in a sufficient yield. Improved purification of heterologous polypeptides from microbial fermentation broths or homogenates is described, for example, in US Pat. No. 7,169,908, the entire disclosure of which is expressly incorporated herein by reference.

収集細胞培養液（ＨＣＣＦ）調製物
ＣＣＦの完全な溶解は、Microfluidics HC-8000 ホモジナイザーを使用して高圧ホモジナイゼーションによって達成した。機器の圧力調整器を４０００−８０００ｐｓｉに設定し、ＣＣＦを、ホモジナイザーを通して引き込み、単一パス後に完全な細胞溶解（膜破壊）を達成した。系に水をパージしたところで、ＣＣＦホモジネートを集めた。ホモジネートを遠心ボトルに移し、２０℃にてSorval RC-3Bローター遠心機で４５００ｒｐｍで３０分間遠心分離した。遠心物をデカントした後、デプスフィルターで濾過し、ついでシリコンチュービングを備えた蠕動ポンプを使用して０．２２μｍの滅菌濾過を施し、ホモジナイズされたＣＣＦ（１００％細胞溶解物）から最終ＨＣＣＦを生成した。別法では、ＣＣＦをホモジナイゼーションなしに発酵槽からそのまま遠心分離した後、遠心物を０．２２μｍの滅菌フィルターで濾過してＨＣＣＦを生成した。
Collecting cell culture fluid (HCCF) complete dissolution of the preparation CCF was achieved by high pressure homogenization using a Microfluidics HC-8000 homogenizer. The instrument pressure regulator was set to 4000-8000 psi and CCF was drawn through the homogenizer to achieve complete cell lysis (membrane disruption) after a single pass. When the system was purged with water, CCF homogenate was collected. The homogenate was transferred to a centrifuge bottle and centrifuged at 4500 rpm for 30 minutes in a Sorval RC-3B rotor centrifuge at 20 ° C. Decant the centrifugate, filter through a depth filter, and then perform 0.22 μm sterile filtration using a peristaltic pump with silicon tubing to produce the final HCCF from homogenized CCF (100% cell lysate) did. In another method, CCF was directly centrifuged from the fermentor without homogenization , and the centrifugate was filtered through a 0.22 μm sterile filter to produce HCCF.

透析実験
透析実験を、オクレリズマブの還元を引き起こす成分が小分子か巨大分子（つまり、酵素）かを決定するために実施した。３ｍＬの精製し製剤化したオクレリズマブの試料（３０．２ｍｇ／ｍＬ）を１Ｌのリン酸緩衝生理食塩水（ＰＢＳ，１０ｍＭ ｐＨ７．２）で２４時間透析し、ＰＢＳを８時間後に変えた。ついで、オクレリズマブ試料の濃度を、２８０ＮＭでの吸光度を使用して１ｍｇ／ｍＬに調節した。アリコートを使用前に−７０℃で保存した。透析チュービングを０．０５％のアジド溶液で一晩水和させ、使用前に滅菌水ですすいだ。３Ｌの発酵槽からＣＣＦのホモジナイゼーションから得られたＨＣＣＦを解凍し、蠕動ポンプを使用して０．２２μｍのＭｉｌｌｉｐａｋフィルターで濾過した。６つの短いミニタンクに３０ｍＬのＨＣＣＦをそれぞれ満たした。各ミニタンクに、密封した透析チュービング内の５００μＬのオクレリズマブ試料を加えた。ミニタンクを密封し、３５ｒｐｍと雰囲気温度で操作するベンチトップミキサー(Barnstead Lab-Line MAX Q 4000)中に入れた。各時点で、一つのミニタンクをミキサーから取り除き、ＨＣＣＦ（ミニタンク中）及びオクレリズマブ試料（透析バッグ中）のアリコートを取り上げて、遊離チオールアッセイ及びバイオアナライザーアッセイ(以下に記載)で分析するまで、−７０℃で保存した。
Dialysis experiments Dialysis experiments were performed to determine whether the component causing the reduction of ocrelizumab was a small molecule or a macromolecule (ie, an enzyme). A 3 mL purified and formulated sample of ocrelizumab (30.2 mg / mL) was dialyzed against 1 L of phosphate buffered saline (PBS, 10 mM pH 7.2) for 24 hours, and the PBS was changed after 8 hours. The concentration of the ocrelizumab sample was then adjusted to 1 mg / mL using absorbance at 280 NM. Aliquots were stored at -70 ° C before use. Dialysis tubing was hydrated overnight with 0.05% azide solution and rinsed with sterile water before use. HCCF obtained from CCF homogenization was thawed from a 3 L fermentor and filtered through a 0.22 μm Millipak filter using a peristaltic pump. Six short mini-tanks were each filled with 30 mL HCCF. To each mini tank was added 500 μL of ocrelizumab sample in sealed dialysis tubing. The mini tank was sealed and placed in a bench top mixer (Barnstead Lab-Line MAX Q 4000) operating at 35 rpm and ambient temperature. At each time point, one mini tank is removed from the mixer, and aliquots of HCCF (in mini tank) and ocrelizumab sample (in dialysis bag) are taken and analyzed in a free thiol assay and bioanalyzer assay (described below). Stored at -70 ° C.

阻害剤添加及び細胞培養液（ＣＣＦ）混合
２５０ｍＭのＥＤＴＡ又は５０ｍＭのＣｕＳＯ４の原液をホモジナイゼーション前のＣＣＦに添加して最終濃度の範囲を評価して、抗体のジスルフィド還元を防止した。最終ＨＣＣＦをホモジナイズされたＣＣＦから生成したところで、希釈し１００％最大以下まで細胞溶解物の全レベルを減少させるためにホモジナイズされていないＣＣＦ（またＥＤＴＡ又はＣｕＳＯ４を含む）から生成したＨＣＣＦとこれら溶液をついで混合した。あるいは、１Ｍの酢酸の原液を週の配合ＨＣＣＦ溶液（ホモジナイズされたＣＣＦ及びホモジナイズされていないＣＣＦ）に加え、抗体のジスルフィド還元を防止するために溶液のｐＨを減少させた。
およそ３０−５０ｍＬの各ＨＣＣＦ溶液（ＥＤＴＡ、ＣｕＳＯ４、酢酸を含むか、又はコントロールでは無添加）を５０ｍＬの３１６Ｌステンレス鋼製バイアルに入れた。バイアルをクランプで密封し、溶液は曝気又は攪拌はしなかった。バイアルを室温（１８−２２℃）で保存した。予め定めた時点で、溶液を取り除き、実験室規模のプロテインＡアフィニティ樹脂で精製した。
同様の結果を、他の酸化剤、例えばシスチン及び酸化型グルタチオンを用いて得ることができる。
Inhibitor addition and cell culture fluid (CCF) mix A stock solution of 250 mM EDTA or 50 mM CuSO 4 was added to the CCF prior to homogenization to assess the range of final concentrations to prevent disulfide reduction of the antibody. Now that generates a final HCCF from homogenized CCF, HCCF with these generated from CCF that are not homogenized in order to reduce the total level of the diluted cell lysate up to 100% or less (also containing EDTA or CuSO 4) The solution was then mixed. Alternatively, a stock solution of 1M acetic acid was added to the weekly formulated HCCF solution ( homogenized CCF and non- homogenized CCF) to reduce the pH of the solution to prevent disulfide reduction of the antibody.
Approximately the HCCF solution 30-50mL (EDTA, CuSO 4, or containing acetic acid, or in the control without addition) were placed in a 316L stainless steel vial 50 mL. The vial was sealed with a clamp and the solution was not aerated or agitated. The vial was stored at room temperature (18-22 ° C.). At predetermined time points, the solution was removed and purified on a laboratory scale protein A affinity resin.
Similar results can be obtained with other oxidizing agents such as cystine and oxidized glutathione.

空気スパージング
抗体のジスルフィド還元を防止するためのホモジナイズされたＣＣＦから生産したＨＣＣＦの空気スパージングを評価するために、３Ｌのガラス製又は１５Ｌのステンレス鋼製容器を利用した。およそ１−５ＬのＨＣＣＦを０．２２μｍで滅菌濾過し、各滅菌容器に入れた。実験条件は、二酸化炭素の添加によってｐＨ制御を伴うか伴わないで１８−２２℃及び５０（１５Ｌ発酵槽）又は２７５ｒｐｍ（３Ｌ発酵槽）に維持した。溶液に空気をスパージングして空気飽和状態まで溶存酸素レベルを増加させるか窒素（コントロール）をスパージングして溶液中の溶存酸素を除去した。各容器へのガス流は、一定の曝気速度が使用されたか又は最小レベルの溶存酸素が維持されたかに応じて変動した。予め定めた時点で、２５−５０ｍＬの試料を両方の容器から取り除き、分析の前に実験室規模のプロテインＡアフィニティ樹脂で精製した。
Air Sparging To evaluate the air sparging of HCCF produced from homogenized CCF to prevent disulfide reduction of antibodies, 3 L glass or 15 L stainless steel containers were utilized. Approximately 1-5 L of HCCF was sterile filtered at 0.22 μm and placed in each sterile container. Experimental conditions were maintained at 18-22 ° C. and 50 (15 L fermentor) or 275 rpm (3 L fermentor) with or without pH control by addition of carbon dioxide. Air was sparged into the solution to increase the dissolved oxygen level to air saturation or nitrogen (control) was sparged to remove dissolved oxygen in the solution. The gas flow to each vessel varied depending on whether a constant aeration rate was used or a minimum level of dissolved oxygen was maintained. At predetermined time points, 25-50 mL samples were removed from both containers and purified with lab-scale protein A affinity resin prior to analysis.

（ｉｉ）ＡＴＧ及びＡＴＭによるＨＣＣＦ中の組換え抗体の還元の阻害
ＴｒｘＲの２種の市販の特異的阻害剤オーロチオグルコース（ＡＴＧ）及び金チオリンゴ酸塩（ＡＴＭ）について、インビトロでＴｒｘ系を阻害しオクレリズマブの還元を阻害するその能力を試験した。ＡＴＧ及びＡＴＭ共、上述のアッセイにおいてオクレリズマブの還元を効果的に阻害することができる（図６及び７を参照）。図５の脚注に記載したものと同じ反応混合物に１ｍＭの濃度でオーロチオグルコース又は金チオリンゴ酸塩を添加すると、バイオアナライザー分析からのゲル様デジタル画像に示されているようにオクレリズマブの還元を効果的に阻害した。
Ｔｒｘ系がＨＣＣＦ中で活性であり、還元オクレリズマブが還元抗体分子を生じる製造実験又は実験室規模の実験で観察されるならば、双方の金化合物（ＡＴＧ及びＡＴＭ）がＨＣＣＦ中のオクレリズマブの還元を阻害することができなければならない。図１０は、インキュベーションの期間後３Ｌの発酵槽から生成したホモジナイズされたＣＣＴからのＨＣＣＦ中においてオクレリズマブが直ぐに還元されたことを示している。しかしながら、オクレリズマブ還元事象は、１ｍＭのＡＴＧかＡＴＭがＨＣＣＦに添加されたときには完全に阻害された（図１１及び１２）。これらの結果は、Ｔｒｘ系がＨＣＣＦにおいて活性であり、オクレリズマブの還元の直接的な原因であることを証明している。
(Ii) Inhibition of reduction of recombinant antibodies in HCCF by ATG and ATM Inhibition of the Trx system in vitro for two commercially available specific inhibitors of TrxR, aurothioglucose (ATG) and gold thiomalate (ATM) It was tested for its ability to inhibit the reduction of ocrelizumab. Both ATG and ATM can effectively inhibit the reduction of ocrelizumab in the above-described assay (see FIGS. 6 and 7). Adding aurothioglucose or gold thiomalate at a concentration of 1 mM to the same reaction mixture as described in the footnote of FIG. 5 is effective in reducing ocrelizumab as shown in the gel-like digital image from the bioanalyzer analysis. Inhibited.
If the Trx system is active in HCCF and reduced ocrelizumab is observed in manufacturing or lab-scale experiments that produce reduced antibody molecules, both gold compounds (ATG and ATM) can reduce ocrelizumab in HCCF. Must be able to inhibit. FIG. 10 shows that ocrelizumab was immediately reduced in the HCCF from the homogenized CCT produced from the 3 L fermentor after the incubation period. However, the ocrelizumab reduction event was completely inhibited when 1 mM ATG or ATM was added to HCCF (FIGS. 11 and 12). These results demonstrate that the Trx system is active in HCCF and is a direct cause of the reduction of ocrelizumab.

実施例７
（ｉ）ＥＤＴＡ、（ｉｉ）硫酸銅、及び（ｉｉｉ）酢酸の添加による組換え抗体の還元の阻害
４種の異なったＨＣＣＦを保存し、ステンレス鋼製バイアルに入れた。溶液は、ホモジナイズされたＣＣＦからのＨＣＣＦをホモジナイズされていないＣＣＦからのＨＣＣＦで希釈することによって生成された細胞溶解物の量では同様であった。例えば、１５０ｍＬの第一溶解溶液を、５０ｍＬの第二溶液とそれぞれ混合した。この研究で評価された４種のＨＣＣＦ混合物は、（１）２０ｍＭのＥＤＴＡ、（２）３０μＭのＣｕＳＯ４、（３）１５ｍＭの酢酸（ｐＨ５．５）の何れかを含んでおり、（４）コントロール溶液には化学的阻害剤は添加しなかった。４種全ての混合物からのオクレリズマブ抗体はプロテインＡクロマトグラフィーを使用して直ぐに（ｔ＝０時間）精製し、ついでステンレス鋼製バイアル中に２０時間及び４０時間保存した後に再び生成した。精製したプロテインＡ溶離プールをバイオアナライザーアッセイによって分析して、インタクトな抗体（１５０ｋＤａ）の割合を定量した。結果は、９０％のインタクトな抗体が初期時点で４種全ての混合物中に存在していることを示している（図１９）。しかしながら、２０時間の時点では、インタクトな抗体はコントロール混合物（添加なし）では検出されず、抗体ジスルフィド結合の還元を示している。他の３種の混合物では、９０％を越えるインタクトな抗体が２０時間及び４０時間の双方の時点でも尚検出されており、試験した３種全ての阻害剤によるジスルフィド結合の還元の防止を証明している。
Example 7
Inhibition of Reduction of Recombinant Antibody by Addition of (i) EDTA, (ii) Copper Sulfate, and (iii) Acetic Acid Four different HCCFs were stored and placed in stainless steel vials. The solution was similar in the amount of cell lysate produced by diluting HCCF from homogenized CCF with HCCF from non- homogenized CCF. For example, 150 mL of the first dissolution solution was mixed with 50 mL of the second solution, respectively. The four HCCF mixtures evaluated in this study contain either (1) 20 mM EDTA, (2) 30 μM CuSO 4 , (3) 15 mM acetic acid (pH 5.5), (4) No chemical inhibitor was added to the control solution. Ocrelizumab antibodies from all four mixtures were purified immediately using protein A chromatography (t = 0 hours) and then regenerated after storage in stainless steel vials for 20 and 40 hours. The purified protein A elution pool was analyzed by bioanalyzer assay to quantify the percentage of intact antibody (150 kDa). The results show that 90% intact antibody is present in all four mixtures at the initial time point (FIG. 19). However, at 20 hours, intact antibody was not detected in the control mixture (no addition) indicating antibody disulfide bond reduction. In the other three mixtures, over 90% intact antibody was still detected at both 20 and 40 hours, demonstrating the prevention of disulfide bond reduction by all three inhibitors tested. ing.

実施例８
ＨＣＣＦの空気スパージングによる組換え抗体の還元の阻害
ホモジナイズされたＣＣＦから生成した一つのＨＣＣＦ混合物を保存し、二つの別個の１０Ｌのステンレス鋼製発酵槽に入れた。一方の容器に空気をスパージすると共に、他方の容器に窒素ガスをスパージした。オクレリズマブ抗体は、プロテインＡクロマトグラフィーを使用して、初期混合物から直ぐに（ｔ＝０時間）精製した。選択された時点で、５０ｍＬの試料を各容器から除去し、抗体をプロテインＡクロマトグラフィーを使用して精製した。ついで、精製したプロテインＡ溶離プールをバイオアナライザーアッセイによって分析して、１５０ｋＤａのインタクトな抗体の割合を定量した。結果は、およそ８５％のインタクトな抗体が初期溶液中に存在していることを示しており（図２０）、酸素への暴露（つまり発酵槽への空気スパージ）の前の抗体ジスルフィド結合のある程度の初期の還元を示している。混合物に２時間の間、空気をスパージすると、３６時間の研究の残りに対して９０％より多いインタクトな抗体が測定された。これに対して、混合物に窒素ガスをスパージした場合は、２時間（２８％の１５０ｋＤａピーク）及び６時間（５％の１５０ｋＤａピーク）に測定したところ抗体還元事象が継続した。これらの結果は、ホモジナイズされたＣＣＦから生成したＨＣＣＦ混合物が酸素に暴露されると、抗体中のジスルフィド結合の還元を防止できることを証明している。

Example 8
Inhibition of recombinant antibody reduction by air sparging of HCCF
One HCCF mixture produced from the homogenized CCF was stored and placed in two separate 10 L stainless steel fermenters. Air was sparged in one container and nitrogen gas was sparged in the other container. The ocrelizumab antibody was purified immediately (t = 0 hours) from the initial mixture using protein A chromatography. At selected time points, 50 mL samples were removed from each vessel and the antibody was purified using protein A chromatography. The purified protein A elution pool was then analyzed by a bioanalyzer assay to quantify the percentage of intact antibody at 150 kDa. The results show that approximately 85% of intact antibody is present in the initial solution (FIG. 20) and some degree of antibody disulfide binding prior to exposure to oxygen (ie, air sparging to the fermentor). Shows the initial reduction of. When the mixture was sparged with air for 2 hours, more than 90% intact antibody was measured over the remainder of the 36 hour study. In contrast, when the mixture was sparged with nitrogen gas, the antibody reduction event continued as measured at 2 hours (28% 150 kDa peak) and 6 hours (5% 150 kDa peak). These results demonstrate that the HCCF mixture produced from homogenized CCF can prevent reduction of disulfide bonds in the antibody when exposed to oxygen.

Claims (25)

組換え真核生物宿主細胞により発現され、分泌される抗体のジスルフィド結合の還元を防止する方法であって、（ａ）アンチセンスヌクレオチドを含む核酸分子又は（ｂ）干渉ＲＮＡにより該真核生物宿主細胞のＴｒｘ系の酵素の発現レベルを減少させること及び分泌された抗体を収集することを含み、それにより収集細胞培養液（ＨＣＣＦ）において、抗体のジスルフィド結合の還元が阻害される方法。 A method for preventing reduction of disulfide bonds in an antibody expressed and secreted by a recombinant eukaryotic host cell, comprising: (a) a nucleic acid molecule comprising an antisense nucleotide or (b) said eukaryotic host with an interfering RNA A method comprising reducing the expression level of a Trx-based enzyme in a cell and collecting the secreted antibody, whereby the reduction of antibody disulfide bonds is inhibited in a harvested cell culture fluid (HCCF). （ａ）アンチセンスヌクレオチドを含む核酸分子又は（ｂ）干渉ＲＮＡによりＴｒｘ系の酵素の発現レベルが減少した組換え真核生物宿主細胞中で抗体を発現し、抗体が分泌されること及び分泌された抗体を収集することを含み、それにより、収集細胞培養液（ＨＣＣＦ）において、抗体のジスルフィド結合の還元が阻害される、抗体を製造するための方法。 The antibody is expressed and secreted in a recombinant eukaryotic host cell in which the expression level of the Trx-based enzyme is reduced by (a) a nucleic acid molecule containing an antisense nucleotide or (b) an interfering RNA. A method for producing an antibody, comprising collecting the antibody, wherein the reduction of the disulfide bond of the antibody is inhibited in a harvested cell culture fluid (HCCF). 酵素が、チオレドキシンレダクターゼ、Ｇ６ＰＤ又はヘキソキナーゼである、請求項１又は２の方法。   The method of claim 1 or 2, wherein the enzyme is thioredoxin reductase, G6PD or hexokinase. 酵素発現レベルが、ｓｉＲＮＡの使用により減少させられる、請求項１又は２の方法。 The method of claim 1 or 2 , wherein the enzyme expression level is reduced by the use of siRNA. 前記ｓｉＲＮＡ又はアンチセンスヌクレオチドが、チオレドキシンレダクターゼ遺伝子配列に特異的に結合する、請求項１、２又は４の方法。 5. The method of claim 1, 2 or 4 , wherein the siRNA or antisense nucleotide specifically binds to a thioredoxin reductase gene sequence. チオレドキシンレダクターゼ遺伝子配列がＣＨＯのチオレドキシンレダクターゼ遺伝子配列である、請求項５の方法。 6. The method of claim 5 , wherein the thioredoxin reductase gene sequence is a CHO thioredoxin reductase gene sequence. 真核生物宿主細胞が哺乳動物宿主細胞である、請求項５の方法。 6. The method of claim 5 , wherein the eukaryotic host cell is a mammalian host cell. 哺乳動物宿主細胞がチャイニーズハムスター卵巣（ＣＨＯ）細胞である、請求項７の方法。 8. The method of claim 7 , wherein the mammalian host cell is a Chinese hamster ovary (CHO) cell. 抗体が、治療用抗体又はその生物学的に機能的な断片である、請求項１から８の何れか一項に記載の方法。 9. The method according to any one of claims 1 to 8, wherein the antibody is a therapeutic antibody or a biologically functional fragment thereof. 治療用抗体の生物学的に機能的な断片が、抗体断片から形成されたＦａｂ、Ｆａｂ′、Ｆ（ａｂ′）２、ｓｃＦｖ、（ｓｃＦｖ）２、ｄＡｂ、相補性決定領域（ＣＤＲ）断片、直鎖抗体、単鎖抗体分子、ミニボディ、ダイアボディ、及び多重特異的抗体からなる群から選択される、請求項９の方法。 A biologically functional fragment of a therapeutic antibody is Fab, Fab ′, F (ab ′) 2 , scFv, (scFv) 2 , dAb, complementarity determining region (CDR) fragment formed from the antibody fragment, 10. The method of claim 9 , wherein the method is selected from the group consisting of a linear antibody, a single chain antibody molecule, a minibody, a diabody, and a multispecific antibody. 治療用抗体又はその生物学的に機能的な断片が、抗ＨＥＲ２抗体；抗ＣＤ２０抗体；抗ＩＬ−８抗体；抗ＶＥＧＦ抗体；抗ＣＤ４０抗体，抗ＣＤ１１ａ抗体；抗ＣＤ１８抗体；抗ＩｇＥ抗体；抗Ａｐｏ−２レセプター抗体；抗組織因子（ＴＦ）抗体；抗ヒトα４β７インテグリン抗体；抗ＥＧＦＲ抗体；抗ＣＤ３抗体；抗ＣＤ２５抗体；抗ＣＤ４抗体；抗ＣＤ５２抗体；抗Ｆｃレセプター抗体；抗癌胎児抗原（ＣＥＡ）抗体；乳房上皮細胞に対する抗体；結腸癌細胞に結合する抗体；抗ＣＤ３８抗体；抗ＣＤ３３抗体；抗ＣＤ２２抗体；抗ＥｐＣＡＭ抗体；抗ＧｐＩＩｂ／ＩＩＩａ抗体；抗ＲＳＶ抗体；抗ＣＭＶ抗体；抗ＨＩＶ抗体；抗肝炎抗体；抗ＣＡ１２５抗体；抗αｖβ３抗体；抗ヒト腎細胞癌抗体；抗ヒト１７−１Ａ抗体；抗ヒト結腸直腸腫瘍抗体；ＧＤ３ガングリオシドに対する抗ヒトメラノーマ抗体Ｒ２４；抗ヒト扁平上皮癌；及び抗ヒト白血球抗原（ＨＬＡ）抗体、及び抗ＨＬＡＤＲ抗体からなる群から選択される、請求項９又は１０の方法。 The therapeutic antibody or biologically functional fragment thereof is anti-HER2 antibody; anti-CD20 antibody; anti-IL-8 antibody; anti-VEGF antibody; anti-CD40 antibody, anti-CD11a antibody; anti-CD18 antibody; Apo-2 receptor antibody; anti-tissue factor (TF) antibody; anti-human α 4 β 7 integrin antibody; anti-EGFR antibody; anti-CD3 antibody; anti-CD25 antibody; anti-CD4 antibody; anti-CD52 antibody; Anti-CD38 antibody; anti-CD33 antibody; anti-CD22 antibody; anti-EpCAM antibody; anti-GpIIb / IIIa antibody; anti-RSV antibody; anti-CMV antibody; antibody against breast epithelial cells; Anti-HIV antibody; anti-hepatitis antibody; anti-CA125 antibody; anti-αvβ3 antibody; anti-human renal cell carcinoma antibody; anti-human 17-1A antibody; Rectal tumor antibodies; GD3 anti-human melanoma antibody to ganglioside R24; anti-human squamous cell carcinoma; is selected from the group consisting of and anti-human leukocyte antigen (HLA) antibodies, and anti-HLADR antibody method according to claim 9 or 10. 治療用抗体又はその生物学的に機能的な断片が、ＨＥＲレセプター、ＶＥＧＦ、ＩｇＥ、ＣＤ２０、ＣＤ１１ａ、ＣＤ４０、又はＤＲ５に結合する、請求項９又は１０の方法。 11. The method of claim 9 or 10 , wherein the therapeutic antibody or biologically functional fragment thereof binds to the HER receptor, VEGF, IgE, CD20, CD11a, CD40, or DR5. 前記ＨＥＲレセプターがＨＥＲ１及び／又はＨＥＲ２である、請求項１２の方法。 13. The method of claim 12 , wherein the HER receptor is HER1 and / or HER2. ＨＥＲレセプターがＨＥＲ２である、請求項１３の方法。 14. The method of claim 13 , wherein the HER receptor is HER2. 前記治療用抗体が、配列番号１６、１７、１８、及び１９からなる群から選択される重鎖及び軽鎖可変ドメイン配列を含む、請求項１４の方法。 15. The method of claim 14 , wherein the therapeutic antibody comprises heavy and light chain variable domain sequences selected from the group consisting of SEQ ID NOs: 16, 17, 18, and 19. 前記治療用抗体がＣＤ２０に結合する抗体である、請求項１２の方法。 13. The method of claim 12 , wherein the therapeutic antibody is an antibody that binds to CD20. 前記治療用抗体が、配列番号１から１５からなる群から選択される重鎖及び軽鎖可変ドメイン配列を含む、請求項１６の方法。 17. The method of claim 16 , wherein the therapeutic antibody comprises heavy and light chain variable domain sequences selected from the group consisting of SEQ ID NOs: 1-15. 前記治療用抗体が、ＶＥＧＦに結合する抗体である、請求項１２の方法。 13. The method of claim 12 , wherein the therapeutic antibody is an antibody that binds to VEGF. 前記治療用抗体が、配列番号２０から２５からなる群から選択される重鎖及び軽鎖可変ドメイン配列を含む、請求項１８の方法。 19. The method of claim 18 , wherein the therapeutic antibody comprises heavy and light chain variable domain sequences selected from the group consisting of SEQ ID NOs: 20-25. 前記治療用抗体がＣＤ１１ａに結合する抗体である、請求項１２の方法。 13. The method of claim 12 , wherein the therapeutic antibody is an antibody that binds to CD11a. 前記治療用抗体が、配列番号２６から２９からなる群から選択される重鎖及び軽鎖可変ドメイン配列を含む、請求項２０の方法。 21. The method of claim 20 , wherein the therapeutic antibody comprises heavy and light chain variable domain sequences selected from the group consisting of SEQ ID NOs: 26-29. 前記治療用抗体がＤＲ５レセプターに結合する、請求項１２の方法。 13. The method of claim 12 , wherein the therapeutic antibody binds to DR5 receptor. 前記治療用抗体が、Ａｐｏｍａｂｓ１．１、２．１、３．１、４．１、５．１、５．２、５．３、６．１、６．２、６．３、７．１、７．２、７．３、８．１、８．３、９．１、１．２、２．２、３．２、４．２、５．２、６．２、７．２、８．２、９．２、１．３、２．２、３．３、４．３、５．３、６．３、７．３、８．３、９．３、及び２５．３からなる群から選択される、請求項２２の方法。 Said therapeutic antibody is Apomabs 1.1, 2.1, 3.1, 4.1, 5.1, 5.2, 5.3, 6.1, 6.2, 6.3, 7.1, 7.2, 7.3, 8.1, 8.3, 9.1, 1.2, 2.2, 3.2, 4.2, 5.2, 6.2, 7.2, 8. From the group consisting of 2, 9.2, 1.3, 2.2, 3.3, 4.3, 5.3, 6.3, 7.3, 8.3, 9.3, and 25.3 23. The method of claim 22 , wherein the method is selected. 前記治療用抗体がＡｐｏｍａｂ８．３又はＡｐｏｍａｂ７．３である、請求項２３の方法。 24. The method of claim 23 , wherein the therapeutic antibody is Apomab 8.3 or Apomab 7.3. 前記治療用抗体がＡｐｏｍａｂ７．３である、請求項２４の方法。 25. The method of claim 24 , wherein the therapeutic antibody is Apomab 7.3.
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